JPS5910355B2 - Manufacturing method of leucyl nitroagmatine compound - Google Patents
Manufacturing method of leucyl nitroagmatine compoundInfo
- Publication number
- JPS5910355B2 JPS5910355B2 JP10759075A JP10759075A JPS5910355B2 JP S5910355 B2 JPS5910355 B2 JP S5910355B2 JP 10759075 A JP10759075 A JP 10759075A JP 10759075 A JP10759075 A JP 10759075A JP S5910355 B2 JPS5910355 B2 JP S5910355B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- leucyl
- nitroagmatine
- manufacturing
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Landscapes
- Epoxy Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明はロイシルニトロアグマチン化合物の製５ 法に
関し、さらに詳しくは一般式▲数式、化学式、表等があ
ります▼
（式中Ｒは低級アルキル基を示す。[Detailed Description of the Invention] The present invention relates to a method for producing a leucylnitroagmatine compound, and more specifically, there are general formulas, numerical formulas, chemical formulas, tables, etc. (In the formula, R represents a lower alkyl group.
）で表わされるロイシルニトロアグマチン化合物の製法
に関す〒般式ＣＨＣＯＮＨ（ＣＨ２）４ＮＨＣＮＨ２
ＣＨ２ＣＨ（ＣＨ３）２Ｎ−Ｎｏ、
−ＨＣＯＮＨ（ＣＨ２）４ＮＣＮＨ２
１１１゜”’
−Ｈ２ＣＨ（ＣＨ８）２Ｎ−Ｎ０２
る。) Concerning a method for producing a leucylnitroagmatine compound represented by the general formula:
５ 本発明の目的化合物（Ｉ）は一般式 （式中Ｒは低級アルキル基を示す。5 The object compound (I) of the present invention has the general formula (In the formula, R represents a lower alkyl group.
）で表わされる化合物を３・５−ジメチル−１−ニトロ
グアニルピラゾール（）と反応させることにより得られ
る。本発明の目的化合物（１）のＲは低級アルキル基、
たとえば、メチル、エチル、プロピル、ブチルなどを意
味する。) is obtained by reacting the compound represented by 3,5-dimethyl-1-nitroguanylpyrazole (). R of the object compound (1) of the present invention is a lower alkyl group,
For example, it means methyl, ethyl, propyl, butyl, etc.
本発明の原料化合物（）は、たとえば、Ｎーカルボベン
ゾキシ一Ｎ５−〔Ｎ−（３−トランス−アルコキシカル
ボニルオキシラン−２−カルボニル）一ロイシル〕−１
・４−ジアミノブタン（）を常温常圧で接触還元させて
定量的に得られる。The starting compound () of the present invention is, for example, N-carbobenzoxy-N5-[N-(3-trans-alkoxycarbonyloxirane-2-carbonyl)-leucyl]-1
- Obtained quantitatively by catalytic reduction of 4-diaminobutane () at room temperature and pressure.
次に上記化合物（）は、たとえば、次の製法により得ら
れる。Ｎ−カルボベンゾキシ一１・４−ジアミノブタン
にＴｅｒｔ−ブトキシカルボニルロイシンＮ−ヒドロキ
シサクシンイミドエステルを縮合させてＮ−（Ｔｅｒｔ
−ブトキシカルボニルロイシル）−Ｎ仁カルボペンゾキ
シ一１・４−ジアミノブタンを得、これに蟻酸を作用さ
せるとＮ−カルボベンゾキシ一Ｎ′一ロイシル一１・４
−ジアミノブタンを得、これにエチルハイドロジエント
ランスーエポキシサクシネートをトリエチルアミンとジ
エチルホスホロシヤニデートの存在下反応させて化合物
（）を得る。Next, the above compound () can be obtained, for example, by the following manufacturing method. N-(Tert
-butoxycarbonylleucyl)-N-carbopenzoxy-1,4-diaminobutane is obtained, and when formic acid is reacted with this, N-carbobenzoxy-1N'-leucyl-1,4
-Diaminobutane is obtained, and this is reacted with ethylhydrodiene trans-epoxysuccinate in the presence of triethylamine and diethylphosphorocyanidate to obtain compound ().
前記エチルハイドロジエントランスーエポキシサクシネ
ートは、たとえば、ジエチルトランス−エポキシサクシ
ネートに冷時当モルのアルカリを作用させると得られる
。The ethyl hydrodiene trans-epoxy succinate can be obtained, for example, by reacting diethyl trans-epoxy succinate with an equimolar amount of alkali when cold.
本発明の目的化合物（１）は、化合物（）と化合物（）
を通常溶媒中で反応させて得られる。The object compound (1) of the present invention is a compound () and a compound ().
Usually obtained by reacting in a solvent.
溶媒としては低級アルコール、たとえばメタノール、エ
タノール、プロパノール、イソプロパノール、環状エー
テルたとえばテトラヒドロフラン、ジオキサン酢酸エチ
ル、ジメチルホルムアミドなどであるがその他本反応に
関与しない溶媒であれば何でも使用できる。反応温度は
６０℃〜１２０℃の範囲が適当である。Examples of the solvent include lower alcohols such as methanol, ethanol, propanol, isopropanol, and cyclic ethers such as tetrahydrofuran, dioxane, ethyl acetate, and dimethylformamide, but any other solvent that does not participate in this reaction may be used. The reaction temperature is suitably in the range of 60°C to 120°C.
本発明はチオールプロテアーゼ阻害作用を有する新規な
Ｎ−〔Ｎ−（３−トランス−カルボキシオキシラン−２
−カルボニル）一ロイシル〕−アグマチン｛Ｍｐｌ７３
〜１７５℃（分解）｝の合成中間体であり、本発明の目
的物（１）自身もチオールプロテアーゼ阻害作用を有す
る。The present invention discloses a novel N-[N-(3-trans-carboxyoxirane-2) which has a thiol protease inhibitory effect.
-carbonyl)-leucyl]-agmatine {Mpl73
~175°C (decomposition)}, and the object (1) of the present invention itself also has a thiol protease inhibitory effect.
次に本発明を実施例により説明する。Next, the present invention will be explained by examples.
実施例 １
Ｎ−〔Ｎ−３−トランス−エトキシカルボニルオキシラ
ン−２−カルボニル）一ロイシル〕−１・４−ジアミノ
ブタン酢酸塩３．２２、トリエチルアミン０．９６？、
および３・５−ジメチル−１−ニトログアニル−ピラゾ
ール１．７４２をエタノール１００ｍ１中３時間煮沸還
流する。Example 1 N-[N-3-trans-ethoxycarbonyloxirane-2-carbonyl)monoleucyl]-1,4-diaminobutane acetate 3.22, triethylamine 0.96? ,
and 1.742 ml of 3,5-dimethyl-1-nitroguanyl-pyrazole are boiled under reflux in 100 ml of ethanol for 3 hours.
エタノールを留去後残渣にエチルエーテルを加え副生し
た３・５−ジメチルピラゾールを抽出除去し残渣を沸騰
酢酸エチルにて抽出する。不溶物を除去し、酢酸エチル
抽出液をＩＭクエン酸水溶液、水で洗滌後芒硝で乾燥し
酢酸エチルを留去する。残渣固体１．５８ｒをシリカゲ
ル３０ｆのカラムにのせ、はじめに酢酸エチルを展開溶
媒として３・５−ジメチル−１−ニトログアニルピラゾ
ールを流出させた後酢酸エチル−アセトン＝２：１で溶
出して得た無色結晶１．３３ｒを熱酢酸エチル−イソプ
ロピルエーテルから再沈殿してＮ−〔Ｎ−（３−トラン
ス−エトキシカルボニルオキシラン−２−カルボニル）
一ロイシル〕−ＮＧ−ニトロアグマチンを無色粉末状晶
として得る（１．２１ｆ、３６％）。Ｍ．ｐ．ｌ３５〜
１４０℃元素分析Ｃｌ，Ｈ，ＯＮ６Ｏ，として、
計算値（％） Ｃ４７．４３、Ｈ７．Ｏ３、Ｎｌ９．５
２実験値（％） Ｃ４７．６７、Ｈ７．ｌ５、Ｎｌ９．
２６ＯＲ−２１．７Ｏ（Ｃ＝０．５０２、エタノール）
ＮＭＲ（ＤＭＳＯ−Ｄ６）δ−０．７５〜１．０（６Ｈ
，１．２２（３Ｈ，．ｔ，．Ｊ７．２Ｈ２、エステル部
ＣＨ，）ＮＣＨ，ＣＨ２ＣＨ！ＣＨ２Ｎ）
２．９〜３．３（４Ｈ，．ＮＣ鳩ＣＨ，ＣＨ，ＣＨｌＮ
）、３．５９、３．７１（２Ｈ，オキシラン環プロトン
）４．１７（３Ｈ１エステル部ＣＨ２、ＮＨＣｌＩＣＯ
）１７４６、１６４３（共にνＣ＝０）〔注〕ＮＧ−ニ
トロはグアニジノ基の２位のＮにニトロ基のついたこと
を意味する。After distilling off the ethanol, ethyl ether is added to the residue to extract and remove by-produced 3,5-dimethylpyrazole, and the residue is extracted with boiling ethyl acetate. Insoluble matter was removed, and the ethyl acetate extract was washed with an IM citric acid aqueous solution and water, dried over sodium sulfate, and ethyl acetate was distilled off. The residual solid 1.58r was placed on a silica gel 30f column, and 3,5-dimethyl-1-nitroguanylpyrazole was first flowed out using ethyl acetate as a developing solvent, and then eluted with ethyl acetate-acetone = 2:1 to obtain the residue. 1.33 r of colorless crystals were reprecipitated from hot ethyl acetate-isopropyl ether to give N-[N-(3-trans-ethoxycarbonyloxirane-2-carbonyl).
Leucyl]-NG-nitroagmatine is obtained as colorless powder crystals (1.21f, 36%). M. p. l35～
As 140℃ elemental analysis Cl, H, ON6O, calculated value (%) C47.43, H7. O3, Nl9.5
2 Experimental value (%) C47.67, H7. l5, Nl9.
26OR-21.7O (C=0.502, ethanol)
NMR (DMSO-D6) δ-0.75~1.0 (6H
, 1.22 (3H, .t, .J7.2H2, ester part CH,)NCH, CH2CH! CH2N) 2.9~3.3 (4H,.NC pigeon CH, CH, CHlN
), 3.59, 3.71 (2H, oxirane ring proton) 4.17 (3H1 ester moiety CH2, NHClICO
) 1746, 1643 (both νC=0) [Note] NG-nitro means that a nitro group is attached to the 2-position N of a guanidino group.
Claims (1)
グアニシルピラゾールと反応させ、一般式▲数式、化学
式、表等があります▼ （式中Ｒは前記と同意義である。 ）で表わされる化合物を得ることを特徴とするロイシル
ニトロアグマチン化合物の製法。[Claims] 1. A compound represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R represents a lower alkyl group) is reacted with 3,5-dimethyl-1-nitroguanisylpyrazole A method for producing a leucyl nitroagmatine compound, which is characterized by obtaining a compound represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R has the same meaning as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10759075A JPS5910355B2 (en) | 1975-09-05 | 1975-09-05 | Manufacturing method of leucyl nitroagmatine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10759075A JPS5910355B2 (en) | 1975-09-05 | 1975-09-05 | Manufacturing method of leucyl nitroagmatine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5233624A JPS5233624A (en) | 1977-03-14 |
| JPS5910355B2 true JPS5910355B2 (en) | 1984-03-08 |
Family
ID=14463001
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10759075A Expired JPS5910355B2 (en) | 1975-09-05 | 1975-09-05 | Manufacturing method of leucyl nitroagmatine compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5910355B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1585105A (en) * | 1976-04-29 | 1981-02-25 | Unilever Ltd | Emulsions |
| JPS55145679A (en) * | 1979-05-02 | 1980-11-13 | Taisho Pharmaceut Co Ltd | Leucylnitroagmatine derivative |
| JPS55145678A (en) * | 1979-05-02 | 1980-11-13 | Taisho Pharmaceut Co Ltd | Preparation of epoxysuccinylleucylagmatine |
| US4530523A (en) * | 1982-01-15 | 1985-07-23 | Proni Industries, Inc. | Unitary cantilever clamp action fitting with a split end |
-
1975
- 1975-09-05 JP JP10759075A patent/JPS5910355B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5233624A (en) | 1977-03-14 |
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